Chronic alcohol consumption is associated with increased hepatic oxidative stress and reduced antioxidant defense resulting in alcohol-induced liver injury. Nucleoside reverse transcriptase inhibitors (NRTI) in combination with non-NRTIs and protease inhibitors have demonstrated their effectiveness as antiretroviral drugs against HIV-1 despite their well-described side-effects, including liver toxicity. While these side-effects are multi-factorial, oxidative stress and mitochondrial DNA damage has been suggested to play a key role. Mitochondrial DNA damage and increased oxidative stress produced by antiretroviral treatment (ART) may be aggravated by alcoholism, as chronic alcohol consumption is associated with increased hepatic oxidative stress and reduced antioxidant defense resulting in alcohol-induced liver injury. We propose to follow a cohort of 260 HIV infected ART naive participants, 65 patients who are being initiated on ART and are heavy alcohol users (Group 1), 65 patients who are being initiated on ART and do not drink alcohol or are moderate alcohol drinkers (Group 2), 65 patients who are early in HIV disease and are not being initiated on ART and are heavy alcohol users (Group 3), 65 patients who are early in HIV disease and are not being initiated on ART and do not drink alcohol or are moderate alcohol drinkers (Group 4), for 2 years. HIV staging (CD4 and viral load) co- morbidities, ART and other treatments will be documented. Questionnaires on demographics, BMI, food intake, and use of micronutrient supplements will be obtained and treated as covariates. ART will be restricted, and co-morbid conditions which are associated with oxidative stress, will be excluded before the baseline visit. Blood will be drawn for oxidative stress (malondialdehyde to indicate lipid peroxidation, protein carbonyls for protein oxidation, 8-hydroxyguanosine for DNA oxidation). Mitochondrial damage will be assessed with quantitative and qualitative changes in mitochondrial DNA content and with plasma lactate. Hepatocellular injury and function will be determined with plasma levels of ALT, AST, platelets, albumin, hyaluronic acid and total and conjugated bilirubin. Plasma antioxidants (glutathione, vitamins A and E, 1 and 2-carotenes, zinc and selenium) will also be determined. This proposal will determine the combined effects of chronic alcohol consumption and antiretroviral therapy on oxidative stress, antioxidant status, mitochondrial toxicity and liver dysfunction to provide the basis for potential preventive therapeutic approaches to protect the liver from alcohol and antiretroviral drug induced injury. PUBLIC HEALTH RELEVANCE: The objective of this proposal is to determine the combined effects of chronic alcohol consumption and antiretroviral therapy on oxidative stress, antioxidant status, mitochondrial toxicity and liver dysfunction, and to determine the effect of increased oxidative stress and nutritional deficiencies that might occur with chronic alcoholism on HIV-associated mitochondrial DNA damage. A better appreciation for alcohol's effects on HIV and liver disease may increase utilization of alcohol cessation interventions, thus improving treatment outcomes and providing the basis for potential preventive therapeutic approaches to protect liver from alcohol and antiretroviral drug-induced liver injury.